Biological Mechanisms of Pain Management in Lumbar Disk Herniation: Focus on Cytokine Correlations and Therapeutic Approaches

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an important and clinically relevant topic: the biological underpinnings of lumbar disc herniation (LDH)-associated pain and the evaluation of therapeutic approaches with reference to inflammatory cytokines. The integration of clinical outcomes (SF-MPQ, ODI) with molecular measurements (IL-1β, IL-6, IL-8, TNF-α, IFN-γ) is commendable and reflects an interdisciplinary perspective that will interest both clinicians and researchers. The manuscript is generally well organized, with a clear abstract, introduction, and discussion. However, several aspects require clarification and improvement before the paper can be considered for publication. These relate to methodological rigor, statistical interpretation, clarity of presentation, and the depth of discussion.

1. The description of patient allocation to conservative vs. minimally invasive groups is unclear. Were participants randomized, or was treatment choice based on clinical indication? This detail is essential to avoid bias.

1. The conservative therapy protocol combines multiple interventions (laser, TENS, ultrasound, magnetotherapy, acupuncture). This multimodal approach makes it difficult to attribute changes in cytokines or pain scores to specific modalities. The authors should discuss this limitation.
2. The claim that conservative treatment leads to reduction in IL-1β and IL-8 is interesting, but the differences do not appear statistically significant according to Table 5. The discussion should reconcile this discrepancy.
3. The conclusion that conservative therapy is “effective” may be overstated given the absence of robust between-group differences and the short follow-up (two weeks). Longer-term outcomes should be mentioned as an unmet need.
4. The authors state that this is the “first evidence” of correlations between IL-1β/IFN-γ after conservative therapy. This claim should be softened unless a comprehensive literature search confirms novelty.
5. Tables are numerous and somewhat difficult to follow. Consider consolidating key results (e.g., cytokine changes) into a figure or heatmap for clearer visualization.
6. Figure 1 (study design) is helpful but could be improved with a clearer schematic timeline of interventions and sample collection.
7. The manuscript is generally readable, but English phrasing should be polished. Examples: “pain in lower part of the spine is among the dominant factors” could be simplified to “low back pain is one of the most common causes of disability.” A thorough language edit is recommended.
8. Abbreviations are sometimes overused or inconsistently introduced (e.g., “ESI TF” for transforaminal epidural steroid injection). Ensure consistency and clarity.
9. The reference list is appropriate and up to date. However, some claims in the discussion could be more tightly linked to some references (for example, doi: 10.3390/biomedicines11102641 doi: 10.1007/s12035-025-04794-9) rather than generalized.

Author Response

Attached is a word document with responses to reviews.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Pain management in lumbar disc herniation involves control on inflammation, reduction nociceptor sensitization, and modulation of neural plasticity to restore normal nerve function and alleviate pain. Understanding these mechanisms governs treatments such as anti-inflammatory medications, nerve blocks, physical therapy, and modulation of neuroplasticity.

            The authors in their study used a strange approach aiming to prove their results.

Comments

1. The language of the paper should be improved. All the repeated statements should be corrected.
2. Abstract should be rewritten as nothing is clear. The conclusion does not support the data presented as results of the study.
3. Lines 54-57: This sentence is not clear. It should be rephrased.
4. Lines 57-92: Each reference should accompany every statement. Other wise it looks like the authors used AI.
5. Line 100, 106: References are required at the end of these sentences.
6. Line 102 The authors should describe in which cases a conservative treatment approach is used?
7. Tables 2,3 4: Table captions should be written in a proper way without any abbreviations.
8. Tables 4, 5, 7, 8 should be removed as only one significant value was presented in Tables 4, 7, 8. Table 5 has no significant data at all. The results of these Tables should be only indicated in the text.
9. Lines 196-197: These data should be described in the results section. This should be corrected.
10. Lines 199-278, 287-305: These descriptions should be moved into Introduction section. In the discussion the authors should compare their own results with that was observed previously. This should be corrected.
11. Section 4.8: As the size of the subgroups is less than 30, the authors should use only non-parametric methods for statistical analyses. This should be corrected.
12. Lines 306-316, Conclusion: The logic of the authors is not clear. It should be clarified.

Comments on the Quality of English Language

1. The language of the paper should be improved. All the repeated statements should be corrected.

Author Response

Attached is a word document with responses to reviews.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

1. The first paragraph in the introduction is very long. Please split it into several shorter paragraphs so the story is easier to follow.
2. You use “Interferential Current (IFS)”. Please explain what the “S” stands for (stimulation or something else) at first mention, as you didn’t explain it.
3. In some places you say each group has 14 patients, but ODI tables show 10 per group. Please explain the difference. Add a short flow chart that shows why data are missing (who dropped out, missing forms, etc.). Say if you used only complete cases.
4. Tables and text sometimes say INF gamma. The correct abbreviation is IFN-γ (interferon-gamma).
5. The follow-up is about 2 weeks. Please soften claims about “effectiveness.” Say clearly that results are short-term and exploratory.
6. For the cytokine measurements, please add kit/catalog numbers and calibration range. Methods say cytokines are in pg/mL, but the tables do not show the units. Please add units to every cytokine table and keep them consistent with methods.
7. Table 2. SF-MPQ should not be only an abbreviation. Please write the full name.
8. Gelatos part (nucleus pulposus) should be gelatinous part (nucleus pulposus).
9. Please add a short, explicit paragraph on study limitations: small sample size, short follow-up (2 weeks), non-randomized design, multiple testing with risk of false positives, missing data for ODI. This helps readers interpret the findings with the right caution.

Author Response

Attached is a word document with responses to reviews.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed all the concerns raised in the previous version of the manuscript. In its current form the article now meets all the publication criteria for IJMS.

Author Response

Comments 1: The authors have addressed all the concerns raised in the previous version of the manuscript. In its current form the article now meets all the publication criteria for IJMS.

Response 1: Thank you for your thoughtful review and kind words. We greatly appreciate your feedback and are pleased to hear that the revisions we made have addressed all the concerns. We are excited that the manuscript now meets the publication criteria for IJMS.

Reviewer 2 Report

Comments and Suggestions for Authors

Comment

1. Lines 195-196: Tables 6 and 7 are referred to but are missing. This should be corrected

Author Response

Comments 1: Lines 195-196: Tables 6 and 7 are referred to but are missing. This should be corrected.

Response 1: Thank you for your comment, now the above has been changed in lines 195-196: instead of Table 6 and Table 7, it now reads Supplementary Table S1 and Supplementary Table S2 and a supplement has been attached to the main manuscript

Author Response File: Author Response.pdf